Studies on the diastereoselective, asymmetric total synthesis of vindoline and the clinically important antitumor drug vinblastine are detailed based on the implementation of a tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles, and a recently developed single step Fe(III)-promoted biomimetic coupling and subsequent oxidation reaction of vindoline with catharanthine. Extensions of these studies to the synthesis and evaluation of vinblastine analogues containing previously inaccessible deep-seated structural changes will be pursued, new insights into the mechanism of the biomimetic Fe(III)-promoted coupling of vindoline with catharanthine will be established further expanding access to unique vinblastine analogues, two new alternatives to existing coupling methods will be examined and developed expanding the range of synthetically accessible vinblastine analogues available for examination, and key insights into the structural features of vinblastine and vincristine integral to their binding to tubulin, inhibition of microtubulin formation, and inhibition of cell mitosis and tumor cell growth will be established. Not only will a fundamental understanding of the structure-function relationships of vinblastine's antitumor properties emerge from the studies, but drugs with improved potency, selectivity, efficacy, and/or tumor resistance profiles can be expected to continue to emerge from the studies. PUBLIC HEALTH RELEVANCE: Fundamentally new approaches to the synthesis of vinblastine and vincristine, clinically employed antitumor drugs, will be developed, unique insights into the mechanism of a key biosynthetic (biomimetic) coupling reaction will emerge from the studies, a fundamental understanding of the interaction of vinblastine/vincristine with its biological target (tubulin) will be defined, and new drugs that further improve on the potency, selectivity, and efficacy of the clinically used natural products will be discovered including those that are active against vinblastine-resistant and multidrug-resistant (MDR) tumors.